Production of orally administrable controlled release medicaments



PRODUCTION OF ORALLY ADMINISTRABLE CONTROLLED RELEASE MEDICAMENTSWilliam E. Gaunt, Shaker Heights, Ohio, assignor to Strong, Cobb andCompany, Hum, Cleveland, Ohio, a corporation of Delaware No Drawing.Application May 29, 1959 Serial No. 816,694

13 (Ilaims. (Q1. 167-82) July 22, 1957, and 741,235, filed June 11,1958, therei have been set forth certain of the significant, basic andimportant considerations relating to pharmaceutical products of thecontrolled release type and in those applications certain new procedureshave been described and claimed which provide products having an unusualamount of versatility and flexibility in their nature so that controlledrelease products can be tailor-made to fit the particular medicamentinvolved and the results desired from its administration. It has furtherbeen pointed out in said application that the extent of water solubilityof various therapeutic agents varies and that such fact can be takeninto account by suitable modification of the procedure to adapt it forthe production of a particular product.

The earlier applications refer to the use of gels of metal soaps andmore specifically of gels of aluminum salts of fatty acids of the 8 to18 carbon atoms using volatile solvents and, in some instances, heat toprepare the gel, subsequently removing the solvent to give asolvent-free dried gel. uniformly dispersed through the matrix of thesolventfree gel.

It has been found, quite unexpectedly, that the aluminum salts of fattyacid such as aluminum tristearate and aluminum octoate can be made toflow under pressure and that when highly compressed these materialsbecome a translucent mass with the appearance of having been transformedinto a gel-like structure similar to that obtained when the volatilesolvent is removed by evaporation from a solvent gel of thecorresponding aluminum fatty acid salt. Thus when an intimate mixture ofa therapeutic material and aluminum tristearate is subjected tocompression, the therapeutic material becomes embedded in the aluminumtristearate which flows around and encloses the particles of therapeuticmaterial in a homogeneous gel-like matrix. The amount of compressiondetermines the efficiency of this operation and one or more successiveapplications of pressure may, in some instances, be utilized to achieveoptimum results. The minimum amount of compression used is that-which issufiicient to form a gel. The compression necessary to transform thealuminum tristearate into the gel-like mass may be applied byconventional slugging techniques, by pressure rolls or by extrusionprocesses, but it is under stood that other methods and means may beused for compressing the mixed powder of therapeutic material andaluminum soap into the gel-like structure. The compressed products maybe broken down into small and uniform particles and used as such fororal administra- The therapeutic material is intimately and 2,928,773 Paiente Mar. 15, 1960 tion. Alternatively, the compressed product may bebroken down into small particles, lubricated with conventionallubricants and compressed into tablets for oral administration.

The invention is illustrated by the following non-limitative examples:

Example I 10 grams of powdered phenmetrazine hydrochloride (Preludin)mesh) are blended with 15 grams of powdered aluminum tristearate (200mesh) and mixing continned sufficiently to ensure uniformity, followingwhich the powder blend is compressed on a standard compression machine.The resultant slug is reduced to 20 mesh particles, lubricated andcompressed into tablets.

On exposure to artificial gastric juice and intestinal fluid, thefollowing release characteristics were obtained:

Cumulative Time Medium Percent Release Hour 1 Gastric Juim 34. 2 Hour 3Intestinal Fluid... 51. 8 Hour 5 d0 72. 6 Hour 7. do 78. 8

Example II 280 grams of powdered hydroxazine hydrochloride are blendedwith 336 grams of aluminum tristearate and when uniformity is achievedthe mixture is compressed into slugs and the slugs broken down intosmall particles through a 26 mesh screen. The particles are lubricatedwith talc and compressed into tablets.

. 0n exposure to artificial gastric juice and intestinal fluid, thefollowing release characteristics are obtained:

Cumulative Time Medium Percent Release Hour 1 Gastric Juice 44. 4 Hour 3Intestinal Fluid..- 69. 6 Hour 5 -...do. 71. 7 Hour 7 .d0- 78.0

Exampl'll] Cumulative Time Medium Percent Release Hour 1 Gastric Juice17. 2 Hour 3 Intestinal Fluid... 37. 5 Hour 5 -..-do. 54. 7 Hour 7 ..do73. 2

Example IV A mixture of parts of powdered acetyl salicylic acid and 6.67parts of aluminum octoate is blended to gether. The uniform mixture iscompressed into hard slugs and the slugs broken down into smallparticles of 20 mesh size and less. After lubrication the particles arecompressed into tablets which, on exposure to artifi,

,cial gasricjuice andartificial intestinal fluid, show the followingrelease characteristics: r

. r Cumulative Time Medium Percent Release Hour 1 Gastric Iuice.' 22.Hour 3.-- Intestinal Fluid... 49. 2 Hour 5 do .s 72. 0 Hour 7 do 93. 2

Example V I I I I tpawara potassium anti iinony tartrate are blendeduniformly, with ltl,75 gramsoi aluminum Example VI 1 3,000 gramsof-l,2-diplienyl-4-(2'-phenylsulfinylethyl)- 3,5-pyrazolidinedione isblended uniformly with a 150 grams of aluminu'mtristearate andslugged.The resulting slugs are reduced to small particles and reslugged inorder to obtain, complete transformation of the aluminum tristearateinto thegehlikestate. The. hard slugs are broken up intosmallparticlesrof 20 mesh size or less, lubricated, withi talc andcompresseduinto tablets. The tablets show the following releasecharacteristics:

Cumulative Time Medium Percent Release Artificial Gastric o. 4

Intestinal Fluid 34. 1

n will enqted i t an ,iustancethere is little release 1 e hls s du in tza r d e -e po e to r fi s 'tl ia e b c 'aeft 9W o ub y-ni diplieriyl-4. (27 phcuylsulfinylethyl) 3,5 pyrazolidinedionein acid medium. p ,1

,It hasalso been round that t h e versatilityrof the procedure can beincreased by its adaptation tqthe manufacture, of sustainedreleaseforms, of therapeutic. materials active in such small .dosag'e rthat it,is impracticalto .pre-

pare a tablet form without the use of some diluent to increase the bulkto compressible size. Suitable diluents have been found to be inertsoluble substances such as sucrose, lactose, mannitol 'etc., themselvesembedded in appropriate proportion in :the aluminum fatty-acid salt,

matrix. Suchdiluentsrare made by blending 1ho1uble substance, suchas'lactose', with-the aluminum soap, such s; um. trist at .subi t ng theb end to compression and reducing thecompresscdmixture. to smallparticles. The finely divided therapeutic material, either ,7

alone or incorporated in a suitable proportion of matrix, is mixed, withthe lactose/aluminum, tristearate gel-like particles and compressed intotablets.

ocnooco up-into small particles (20 mesh or less) and slugged again toensure that the lactose is unifromly embedded in the aluminumtristearate mixture. The resultant compressed product is broken downinto particles of 20 mesh or less. 5

1 gram of prednisolone (60 mesh) is intimately mixed with 48.;5 grams ofthe above lactose/aluminum tristearate particles and the whole mixturelubricated with Di gram of magnesium stearate. The mixture is compressedinto tablets weighing 250 mg., and containing 5 mg. each ofprednisolone. On exposure to artificial gastric juice and artificialintestinal juice, the following release data were obtained:

materials are blended together and lubricated with 0.75 gram of talc and0.5 gram of magnesium stearate. The mixture is compressed into tabletsweighing 200 mg, containing 32.5 mg. of phenobarbital in each tablet.

Onexposure to artificial gastric juice and artificial intestinal fluid,the following release data were obtained:

' Cumulative Time Medium Percent l Release Gastric Juice l8. 1Intestinal Flu 40. 2 d0 66. 4 do 97. 4

The procedure of the present invention is particularly advantageous ,fortherapeutic materials like acetylsalicylic acid, phenmetrazinehydrochloride, hydroxyzine hydrochloride-and potassium antimonytartrate, but is in no waylimited thereto asthe procedure can be appliedto a, great variety ,of therapeutic agents and makes possible theproviding of a desired release pattern of reproducible character. E. I

It;is understood that the present invention is not limited to *theuse ofaluminum tristearate and aluminum octoate, although these arepreferred,-since other metal soaps of higher fatty acids containing 8 to18 carbon atoms can likewise be used satisfactorily.

.-;The-.present invention is especially characterized by the unique:fact that thergel or gel-like structure is produced by compression inthe absence of a volatile solvent.= r r; a

;,The particles .orgranules-resulting from the subdividing of the gelorgcl-like structure are usable as such or in hardrshell gelatinecapsules or the particlesor granules are formed intoltabletst Allzoi'these dosage forms are adapted for oral. administration.

What is-claimedis: w; a.

,.1. A method for the. production. of orally administrable controlledrelease medicaments which comprises subjecting a therapeutic-materialand at least about 5%, based 1 onthe, weight oi the therapeuticmaterial, of a metal soup of, an- 8, to lS, carbon atom fattyacid tocompression sufiicient to-form a gel in which the therapeuticmaterial isembedded and subdividing the gel thus formed into granules; H a

,2. The method of claim aluminum tristearate, r v,

1 in which the metal soap is e method of claim 1 in which the ntetalsoap is m octoate;

4. The method of claim 1 in which compression is effected by means ofslugging.

5. The method of claim 1 in which the granules are combined withlubricants and compressed into tablets.

6. The method of claim 5 in which the therapeutic material isphenmetrazine hydrochloride.

7. The method of claim 5 in which the therapeutic material ishydroxazine hydrochloride.

8. The method of claim 5 in which the therapeutic material ismeprobarnate.

9. The method of claim 5 in which the therapeutic material is acetylsalicylic acid.

10. The method of claim 5 in which the therapeutic material is potassiumantimony tartrate.

11. The method of clm'm 5 in which the therapeutic material is1,2-diphenyl-4-(2'-phenylsulfinylethyl)-3,5 pyrazolidinedione. f

12. The method of claim 1 in which the metal soap is mixed with aninert, soluble bulk-increasing diluent prior to compression. $1

. 6 I 13. The method of claim 12 in hi the diluent is powdered lactose.

References Cited in the file of this patent UNITED STATES PATENTS OTHERREFERENCES Am. Drug Index, 1958, J. B. Lippincott Co., Phila. andMontreal, pp. 10, 58, 80 and 496, 495.

20 Merck Index, 6th ed., 1952, pp. 559-560.

1. A METHOD FOR THE PRODUCTION OF ORALLY ADMINISTRABLE CONTROLLED RELEASE MEDICAMENTS WHICH COMPRISES SUBJECTING A THERAPEUTIC MATERIAL AND AT LEAST ABOUT 5%, BASED ON THE WEIGHT OF THE THERAPEUTIC MATERIAL, OF A METAL SOAP OF AN 8 TO 18 CARBON ATOM FATTY ACID TO COMPRESSION SUFFICIENT TO FORM A GEL IN WHICH THE THERAPEUTIC MATERIAL IS EMBEDDED AND SUBDIVIDING THE GEL THUS FORMED INTO GRANULES. 